Dose intensity for bolus versus infusion chemotherapy administration: Review of the literature for 27 anti-neoplastic agents

Problem: The dose intensity (DI) and the maximum tolerated dose (MTD) of anti-neoplastic agents is assumed to be a critical factor for achieving optimal therapeutic benefit. Each of these factors may be influenced by the schedule of drug administration, specifically infusional or bolus delivery. Objective: To review the literature for selected antineoplastic drugs to analyze the relative DI and MTD for bolus vs. infusional administration schedules. Methods: Clinical reports of bolus and infusional delivery of chemotherapeutic drugs in the categories of antimetabolites; alkylating agents; antibiotics; plant alkaloids and platinum analogues were collected focusing on phase I studies establishing the MTD per cycle and the DI. Infusional schedules were defined as continuous parenteral administration for more than 24 hours or, in some instances, daily bolus dosing for one hour for 3 to 5 days. Bolus schedules were defined as administration over minutes up to 24 hours and also included daily dosing in some cases. Results: For antimetabolites, the infusional schedule generally decreases the MTD and DI relative to bolus administration but for 5-FU, the MTD and DI both increase. For alkylating agents and the platinum analogues, the MTD and DI for bolus and infusional delivery are generally comparable; but infusional administration results in a slightly increased MTD for thiotepa and for ifosfamide, the MTD is increased depending upon the duration of the infusion. For the antibiotics and the plant alkaloids, the MTD and DI of infusional administration is variable related to the specific agent and the infusion duration and may be increased, decreased or comparable to the MTD of bolus schedules. Conclusions: The MTD and DI for most cytotoxic agents administered by bolus versus infusional schedules is unpredictable and variable and is influenced by the infusion duration and the interval between treatment cycles (for example three versus four week intervals). The MTD and DI increase substantially with infusional delivery for thiotepa, 5-FU and VM26 (the latter in leukemia specifically) and decrease substantially for the antimetabolites FUDR, ara-C, methotrexate and 6MP. For most other agents and in all four drug categories, the MTD and DI are relatively comparable although for ifosfamide and topotecan, the duration of infusion determines whether the MTD and DI increases, decreases or stays the same relative to bolus administration. The use of cytokines may substantially change the MTD and DI especially for bolus administration since dose limiting toxicity is hematologic for many agents.